The general objective of this project is to define the mechanisms by which human lymphoid cells interact with antigen-presenting cells in order to produce and regulate immune responses. Over the past year, there have been two major efforts underway that are targeted on this objective: 1) dissection of the molecular basis of viral peptide binding and presentation for T-cell recognition by HLA class I molecules; and 2) analysis of expressed T-cell repertoires specific for myelin basic protein (MBP) in MS patients. The principle findings are as follows: 1) isolation and sequencing of endogenous peptides bound to the HLA class I molecules HLA-A1, A3, and HLA-B8 has permitted identification of specific combinations of peptide anchor residues which can be used to successfully predict immunogenic T-cell epitopes within viral protein sequences that are presented by each of these HLA class I molecules; and 2) analysis of T-cell receptor usage in T-cell responses to MBP by genetically identical twins who are concordant or discordant for MS indicates that disease severity may be associated with increased heterogeneity of MBP-specific T cells and could reflect an impaired ability of the immune system to down-regulate these antiself responses.